Alcoholism and alcohol use disorders represent a major public health problem, and are associated with devastating social and economic burdens. Despite active research and development of pharmacotherapies for the treatment of alcoholism, FDA-approved medications are often insufficient in sustaining long-term abstinence in treatment-seeking individuals. This stark reality is made clear by the fact that upwards of 90% of alcoholics relapse at least once over a four year period following treatment onset. The purpose of this project is to establish a new paradigm for the treatment of alcoholism and alcohol use disorders; one that site- specifically targets a neuro-regenerative process, reverses dependence-associated deficits in reward pathway function, circumvents the reliance on protracted patient compliance, and exhibits a permanent effect once introduced. We believe that gene therapy that culminates in the overexpression of glial-derived neurotrophic factor (GDNF) within the ventral tegmental area (VTA), a key component of the reward neurocircuitry, is such a treatment paradigm. Preliminary work conducted in rodents indicated that elevated expression of intra-VTA GDNF blocks the escalation of alcohol drinking in naive animals and significantly attenuates excessive drinking in alcohol-experienced animals whereas suppression of endogenous GDNF in the VTA enhances the progression to heavy alcohol use. A crucial next step in advancing the translation application of this treatment paradigm to human alcoholics is to first demonstrate that a similar intervention in non-human primates (NHPs) will yield a comparable benefit in reducing relapse risk. Aim 1 of this project will establish heavy alcohol self- administration in a cohort of male cynomolgus monkeys during a 6-month open access period. These methods have been validated and replicated for over a decade, with monkeys developing binge-like drinking patterns of alcohol use that resemble those observed in human alcoholics. Aim 2 will evaluate the efficacy of GDNF gene therapy in preventing relapse and the continuation of heavy drinking. An adeno-associated virus serotype 2 (AAV2)-GDNF or control vector will be bilaterally infused into the VTA of each monkey following a 1-month period of abstinence, and alcohol will be re-introduced under open access conditions and self- administration patterns will be monitored during multiple withdrawal-relapse cycles. We hypothesize that AAV2-GDNF treatment will prevent relapse-like drinking patterns and reduce the number of heavy drinking days by attenuating the incidence of binges (large bout sizes) that produce intoxicating blood alcohol concentrations. In summary, we believe this will be a transformative approach for the treatment of alcoholism that may also be applicable for the treatment of other life-threatening addictions. If successful, then our in-life data will be includd in a briefing package to the U.S. Food & Drug Administration in order to advance this candidate therapeutic through an Investigation New Drug (IND) submission for future clinical testing.